Diabetes is truly a silent killer, whose human and economic costs to the U.S., and the world is vastly under-appreciated. Major complications of diabetes include heart disease, stroke, high blood pressure, kidney disease, blindness, nervous system damage, and amputations. As such, diabetes represents the fifth-deadliest disease in the United States. In 2007 alone, diabetes was estimated to cost the U.S. $174 billion dollars. The key to preventing or at least minimizing the complications of diabetes is glycemic control. Implantable glucose sensors, including sensor based closed loop systems, hold the greatest promise for preventing the devastating complications and economic costs of diabetes. Unfortunately, the development of long-term implantable glucose sensors has been hampered in large part by bio-fouling of the implanted sensor by the tissue reactions associated with sensor-induced foreign body reactions, including inflammation, fibrosis and vessel regression. The key role of Monocyte Related Cells (MRCs) including macrophages (MQs), dendritic cells (DCs), and multi-nucleated giant cells (GCs) in controlling inflammation, angiogenesis, fibrosis and vessel regression in foreign body reactions is well established in a variety of diseases and implantable biomaterials. Although MRCs are known to be present at sites of sensor implantation, the roles of these cells in controlling sensor function directly (biofouling of sensor) and/or indirectly by controlling tissue, reactions (inflammation, angiogenesis and fibrosis) remain to be dissected. The goal of this research is not only to determine the contribution of MRCs and their products to the in vivo loss of sensor function, but also to develop strategies and tools that can extend glucose sensor lifespan in vivo by targeting macrophages and their products at sites of sensor implantation.